Rogue proliferation versus restorative protection: where do we draw the line for Wnt and forkhead signaling? - PubMed (original) (raw)

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Rogue proliferation versus restorative protection: where do we draw the line for Wnt and forkhead signaling?

Kenneth Maiese et al. Expert Opin Ther Targets. 2008 Jul.

Abstract

Background: Disease entities such as diabetes, neurodegeneration and cardiovascular disorders affect a significant portion of the world's population.

Objective: Given that cellular survival and longevity in multiple disorders are tied to oxidative stress, apoptotic cell injury and immune system deregulation, the development of robust therapeutic strategies rests heavily upon the ability to balance each of these parameters.

Methods: Here we discuss two exciting signaling pathways, namely Wnt and mammalian forkhead transcription factors predominantly of the O class superfamily, which can share integrated cytoprotective pathways during oxidative stress but may also adversely influence cellular survival and promote cancer cell proliferation.

Conclusion: Future investigations must elucidate the cellular determinants that govern the ability of Wnt and forkhead proteins to promote cellular longevity and possible disease remission but also allow for detrimental biological consequences and clinical compromise.

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Conflict of interest statement

Declaration of interest

The authors declare no conflicts of interest and have received no payment for preparation of this manuscript.

Figures

Figure 1

Figure 1. Wnt signaling is mediated through the β-catenin (canonical) and the calcium (non-canonical) pathways

A representative schematic for the pathways is shown. The canonical Wnt signaling pathway is referred to as the Wnt/β-catenin pathway since it can regulate β-catenin. All Wnt signaling pathways are initiated by interaction of Wnt proteins with Frizzled (FZD) receptors. Once Wnt protein binds to the FZD receptor and the co-receptor low-density lipoprotein receptor-related protein (LRP)-5/6, this is followed by recruitment of Dishevelled. Dishevelled can inhibit glycogen synthase kinase (GSK-3β) activity. The non-canonical or calcium Wnt signaling pathway has two intracellular signaling cascades that consist of the Wnt/Ca2+ pathway and the Wnt/planar cell polarity (PCP) pathway. In the Wnt/Ca2+ pathway, Wnt protein binds to FZD receptors on the cell surface resulting in several cellular processes that can involve stimulation of heterotrimeric G proteins and increased intracellular Ca2+ release. Yet, the distinction between these pathways is sometimes not distinct and may involve non-canonical pathways, such as Wnt5a, that antagonize canonical pathways by leading to the degradation of β-catenin. Lef: Lymphoid enhancer-binding factor; Tcf: T cell factor.

Figure 2

Figure 2. FoxO proteins function during oxidative stress to determine cell proliferation, apoptosis, immune system function, longevity, and tumorigenesis

During stimuli such as oxidative stress, FoxO can be linked to a number of pathways that directly modulate FoxO activity, such as protein kinase B (Akt), the IκB kinase (IKK) pathway, and NF-κB, or that require FoxO to ultimately determine several cellular processes such as cell cycle regulation, apoptosis, immune system modulation, and malignancy.

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